The Sarcodictyins A (7) and B (8) (FIG. 1) were discovered by Pietra et al. in the Mediterranean stoloniferan coral Sarcodictyon roseum and first reported in 1987 (D'Ambrosio et al. Helv. Chim. Acta 1987, 70, 2019-2027; D'Ambrosio et al. Helv. Chim. Acta 1988, 71, 964-976). Sarcodictyins C-F were subsequently disclosed by the same group (D'Ambrosio et al. Helv. Chim. Acta 1988, 71, 964-976).
Eleutherobin was isolated from an Eleutherobia species of soft coral (possibly E. albiflora Alcynacea, Alcyoniidea collected from the Indian Ocean near Bennett's Shoal in Western Australia) by Fenical et al. and first reported in 1995 (Fenical et al. U.S. Pat. No. 5,473,057, Dec. 5, 1995).
Eleuthosides A (5) and B (6) were isolated from an Eleutherobia aurea species of soft coral (collected near the Kwazula-Natal coast of South Africa) and reported by Kashman et al. (Ketzinel et al. J. Nat. Prod. 1996, 59, 873-875). These substances are closely related to eleutherobin (4).
Valdivone (6) was first reported by Kennart and Watson (Lin et al. Tetrahedron 1993, 49, 7977-7984). These substances are also related, both structurally and with regards to their biological action, to eleutherobin (4) and to eleuthosides A (5) and B (6) (FIG. 1).
All four of the above marine-derived natural products (4-8) share the same mechanism of action with the soil-derived (myxobacteria) epothilones A (2) and B (3) (FIG. 1) and the forest-residing Taxol.TM. (1) (FIG. 1). (Lindel et al. J. Am. Chem. Soc. 1997, 119, 8744-8745; Long et al. Cancer Res. 1998, 58, 1111-1115). This mechanism involves tubulin polymerization and microtubule stabilization.
What is needed are synthetic analogs of sarcodictyin A and B, eleutherobin having enhanced bioactivity, and synthetic methods for producing these natural products and their bioactive analogs.